Wednesday, August 29, 2018
Adverum Biotechnologies says IND active for macular degeneration med
Adverum Biotechnologies announced its Investigational New Drug application is active for the planned multi-center, open-label, Phase 1, dose-escalation study of ADVM-022, a novel gene therapy candidate for the treatment of wet age-related macular degeneration. “We are excited to have this IND active for ADVM-022, currently the only intravitreal gene therapy candidate entering the clinic for patients with wet AMD,” said Leone Patterson, interim president and chief executive officer of Adverum Biotechnologies. “We have partnered with leading retinal specialists in the U.S. and look forward to initiating the new OPTIC clinical trial in the fourth quarter of this year.”
https://bit.ly/2NAzP0E
Amgen gets EU OK for leukemia med expansion to peds
Amgen (NASDAQ:AMGN) today announced that the European Commission (EC) has approved an expanded indication for BLINCYTO® (blinatumomab) as monotherapy for the treatment of pediatric patients aged one year or older with Philadelphia chromosome-negative CD19 positive B-cell precursor acute lymphoblastic leukemia (ALL), which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation. The approval is based on results from the Phase 1/2 ‘205 study, an open-label, multicenter, single-arm trial which evaluated the efficacy and safety of BLINCYTO in pediatric patients with relapsed or refractory B-cell precursor ALL.
“Historically, children with relapsed or refractory ALL have had limited pharmacologic options beyond chemotherapy, resulting in poor outcomes,” said David M. Reese, M.D., executive vice president of Research and Development at Amgen. “This approval for BLINCYTO provides physicians across Europe with an important new immunotherapy option for these young, heavily pretreated patients, delivering on Amgen’s commitment to making a difference in the lives of cancer patients.”
ALL is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.1,2 In Europe, an estimated 5,000 children are diagnosed with ALL each year.3
BLINCYTO is the first-and-only bispecific T cell engager (BiTE®) immunotherapy construct approved globally. It is also the first immunotherapy from Amgen’s BiTE® platform, an innovative approach that helps the body’s immune system target cancer cells.
Approval via the centralized procedure grants a marketing authorization from the EC, which is valid in all European Union (EU) and European Economic Area (EEA)-European Free Trade Association (EFTA) states (Norway, Iceland and Liechtenstein).
Better understanding possible regeneration after brain/spinal injury
Researchers at Boston University School of Medicine (BUSM) have uncovered new information on the pathways involved in neuronal regeneration, hopefully bringing the medical community one step closer to managing brain and spinal cord injuries.
By observing neurons after injury, they found that by changing the levels of sugars that cover the surface of proteins (called O-GlcNAc modifications), they could alter neuronal metabolism and thus were able to significantly enhance neuronal regeneration after injury.
Using an experimental model, the researchers compared neurons in which O-GlcNAc levels were either absent or in abundance. The researchers then used a specially designed laser to injure individual neurons and measure subsequent regeneration in each of these conditions.
They surprisingly found that a change in the levels of O-GlcNAc, either as a reduction or an increase, resulted in an enhanced capacity of the neurons to regenerate. The researchers further demonstrated that this can occur by altering the neuron’s metabolism during regeneration and shows the importance of the role of O-GlcNAc in coordinating the response to neuronal injury and regeneration.
The researchers believe there are potentially important clinical implications from this study that could significantly impact conditions like spinal cord injuries. “Using this as a model, we can now find other genes or drugs that act on metabolism to ultimately enhance regeneration and recovery after traumatic neuronal injury,” explained corresponding author Christopher V. Gabel, PhD, associate professor of Physiology and Biophysics at BUSM.
These findings appear in the journal Cell Reports.
Funding for this study was provided by the National Institutes of Health National Institute of Neurological Disorders and Stroke R01 NS077929 (C.V.G., M.R.A.) and the Ruth L. Kirschstein National Research Service Award F31 NS095464 (D.G.T.).
Story Source:
Materials provided by Boston University School of Medicine. Note: Content may be edited for style and length.
Journal Reference:
- Daniel G. Taub, Mehraj R. Awal, Christopher V. Gabel. O-GlcNAc Signaling Orchestrates the Regenerative Response to Neuronal Injury in Caenorhabditis elegans. Cell Reports, 2018; 24 (8): 1931 DOI: 10.1016/j.celrep.2018.07.078
New way to break cancer’s vicious cycle
University of Toronto researchers have uncovered why some cancers grow faster than others. The team led by Liliana Attisano, Professor in U of T’s Donnelly Centre for Cellular and Biomolecular Research, has identified a protein called NUAK2, which is produced by cancer cells to boost their proliferation and whose presence in tumours is associated with poor disease prognosis. Writing in the journal Nature Communications, the researchers show that blocking NUAK2 slows down cancer cell growth raising hopes that a drug could be developed to treat patients.
“We looked at bladder cancer and found that a subset of patients have high levels of NUAK2 protein in their tumours which also happened to be high-grade tumours,” says Attisano, who is also a professor in U of T’s Department of Biochemistry.
Mandeep Gill, a graduate student in Attisano’s lab, first found NUAK2 while looking for a way to block the known cancer-promoting proteins called YAP and TAZ (YAP/TAZ). Highly active in many cancers, YAP/TAZ work by latching onto the DNA to switch on genes that promote cell proliferation. NUAK2 turned out to be one of the genes that was switched on by YAP/TAZ; and unexpectedly it was found to encode a protein that helps shuttle even more YAP/TAZ into the cell’s nucleus, where the DNA is stored, to further bolster abnormal cell growth.
Because YAP/TAZ are active in many cancers, including the aggressive forms of breast and bladder cancer, the researchers wondered if NUAK2 too was elevated in tumour biopsies taken from patients with bladder cancer. They found that NUAK2 was present at high levels in some of the tumours and that those came from patients whose cancer progressed to a more aggressive type.
Fortunately, the flip side is that when NUAK2 is blocked, YAP/TAZ can no longer enter the nucleus. This keeps YAP/TAZ away from the DNA and breaks the vicious cycle by which cancer reinforces itself.
YAP/TAZ belong to the so-called Hippo pathway, a network of proteins that are important for normal cell and tissue growth but which often goes haywire in cancer. The pathway was named after its role in controlling organ size so that organs grow abnormally large, or “hippo-like,” when the pathway breaks down.
Although the Hippo pathway, which normally keeps cell proliferation in check, is inactivated in many cancers, so far there was no good way to target it with drugs. The discovery of NUAK2 changes this.
By blocking NUAK2 protein, either by drugs or by muting the gene that encodes it, the researchers were able to slow down expansion of breast cancer cells in the dish and to shrink breast tumours in mice, respectively. A similar approach could target high-grade tumours in patients.
“If you check the patient’s tumour and if they have high levels of NUAK2 protein, we could maybe treat them with NUAK2 inhibitors.”
In collaboration with Rima Al-awar, Director of Drug Discovery Program at the Ontario Institute for Cancer Research, Frank Sicheri and Jeff Wrana at the Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Attisano is working to develop the anti-NUAK2 compound into a form in which it can be used on animals to further validate the target.
“The ultimate goal is to find a drug that would work on people” Attisano said.
Story Source:
Materials provided by University of Toronto. Note: Content may be edited for style and length.
Journal Reference:
- Mandeep K. Gill, Tania Christova, Ying Y. Zhang, Alex Gregorieff, Liang Zhang, Masahiro Narimatsu, Siyuan Song, Shawn Xiong, Amber L. Couzens, Jiefei Tong, Jonathan R. Krieger, Michael F. Moran, Alexandre R. Zlotta, Theodorus H. van der Kwast, Anne-Claude Gingras, Frank Sicheri, Jeffrey L. Wrana, Liliana Attisano. A feed forward loop enforces YAP/TAZ signaling during tumorigenesis. Nature Communications, 2018; 9 (1) DOI: 10.1038/s41467-018-05939-2
Ketamine activates opioid system to treat depression
A new study appearing online today from the American Journal of Psychiatry finds that ketamine’s acute antidepressant effect requires opioid system activation, the first time that a receptor site has been shown in humans to be necessary for any antidepressant’s mechanism of action. While opioids have been used historically to treat depression, they are known to carry a high risk of dependence. Alan F. Schatzberg, M.D., who led this research at Stanford, cautions against widespread and repeated use of ketamine for depression treatment until more research can be done on both the mechanism of action and the risk of tolerance, abuse and dependence.
Previous research has found ketamine to have rapid-onset antidepressant effects. While the specific mechanism of action for these effects was unknown, it had been generally thought to be due to NMDA receptor antagonism. Since many efforts to develop NMDA antagonists as antidepressants have been unsuccessful, this new study aimed at determining the role of the opioid system in ketamine’s antidepressant and dissociative effects in adults with treatment-resistant depression.
Nolan R. Williams, M.D., and Boris D. Heifets, M.D., Ph.D., from Stanford University, co-first authors of the article, hypothesized that ketamine’s antidepressant effects may be related to intrinsic opioid receptor properties of ketamine. The study looked at whether use of naltrexone, an opioid blocker, prior to ketamine treatment would reduce the acute antidepressant effects of the ketamine or its dissociative effects. The researchers conducted a randomized double-blind crossover trial involving individuals with treatment resistant depression. Participants received the opioid blocker or a placebo prior to ketamine infusion treatment. Twelve participants completed both conditions in randomized order.
Use of naltrexone dramatically blocked the antidepressant effects of the ketamine but not the dissociative effects, so the trial was halted at the interim analysis. Participants receiving the ketamine plus naltrexone experienced much less reduction in depression symptoms than participants receiving ketamine plus placebo. There were no differences in ketamine-induced dissociation between those receiving naltrexone or a placebo.
In an accompanying editorial in the American Journal of Psychiatry, Mark S. George, M.D., with the Medical University of South Carolina and the VA Medical Center in Charleston, S.C., notes, “We would hate to treat the depression and suicide epidemics by overusing ketamine, which might perhaps unintentionally grow the third head of opioid dependence.” George cautions that “with these new findings, we should be cautious about widespread and repeated use of ketamine before further mechanistic testing has been performed to determine whether ketamine is merely another opioid in a novel form.”
George also suggests more attention to other underused treatments for depression and suicidality, including electroconvulsive therapy, transcranial magnetic stimulation and cervical vagus nerve stimulation.
Story Source:
Materials provided by American Psychiatric Association. Note: Content may be edited for style and length.
Journal Reference:
- Nolan R. Williams, Boris D. Heifets, Christine Blasey, Keith Sudheimer, Jaspreet Pannu, Heather Pankow, Jessica Hawkins, Justin Birnbaum, David M. Lyons, Carolyn I. Rodriguez, Alan F. Schatzberg. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. American Journal of Psychiatry, 2018; appi.ajp.2018.1 DOI: 10.1176/appi.ajp.2018.18020138
On the horizon: An acne vaccine
A new study published in the Journal of Investigative Dermatology reports important steps that have been taken towards the development of an acne vaccine. The investigators demonstrated for the first time that antibodies to a toxin secreted from bacteria in acne vulgaris can reduce inflammation in human acne lesions.
“Once validated by a large-scale clinical trial, the potential impact of our findings is huge for the hundreds of millions of individuals suffering from acne vulgaris,” explained lead investigator Chun-Ming Huang, PhD, Department of Dermatology, University of California, San Diego. La Jolla, CA, USA, and Department of Biomedical Sciences and Engineering, National Central University, Jhongli, Taiwan. “Current treatment options are often not effective or tolerable for many of the 85 percent of adolescents and more than 40 million adults in the United States who suffer from this multi-factorial cutaneous inflammatory condition. New, safe, and efficient therapies are sorely needed.”
Even though acne is not a life-threatening disease, its psychological burden is high. It is difficult to conceal and frequently impairs the self-esteem of affected individuals, especially during adolescence — a period of important physical, emotional, and social development. Acne lesions and/or scars may persist in adults. Current medications are often insufficient and can cause difficult-to-tolerate side effects ranging from skin dryness and irritation, to depression, suicidal thoughts, and increased rates of birth defects. An acne vaccination could circumvent potential adverse effects of topical or systemic retinoids and antibiotics, the current treatment options.
This vaccine would be the first to target bacteria already in human skin, instead of invading pathogens. After first demonstrating that Christie-Atkins-Munch-Peterson (CAMP) factor, a toxin secreted from the Propionibacterium acnes (P. acnes) bacteria, can induce inflammatory responses, the investigators explored in mice and ex vivo in human skin cells whether they could inhibit inflammation by employing antibodies to neutralize this virulence factor. Their findings show that the application of monoclonal antibodies to CAMP 2 factor did indeed decrease the inflammatory response.
Both the significance of the findings and the need for continuing research were expressed in an accompanying commentary. “While addressing an unmet medical need and providing an appealing approach, acne immunotherapies that target P. acnes-derived factors have to be cautiously designed to avoid unwanted disturbance of the microbiome that guarantees skin homeostasis. Whether or not CAMP factor-targeted vaccines will impact multiple P. acnes subtypes and other commensals has to be determined, but acne immunotherapy presents an interesting avenue to explore nonetheless,” wrote Emmanuel Contassot, PhD, Dermatology Department, University Hospital and Faculty of Medicine of the University of Zürich, Zürich, Switzerland.
The choice of the antigen to be targeted is critical, not only as a determinant of the efficacy of the vaccine, but also to minimize possible unintended effects or cross-reactivity impairing the microbial equilibrium and skin barrier homeostasis. Future studies will address these factors and focus on engineering a non-toxic chemical or targeted vaccine formulation for its human application.
The findings support P. acnes CAMP factor as a promising target for acne immunotherapy. This is an important observation since CAMP factor had not been previously implicated in the pathogenesis of acne vulgaris. The study also provided a human acne model using acne biopsies, as there is not a fully satisfactory animal model for acne studies.
Story Source:
Materials provided by Elsevier. Note: Content may be edited for style and length.
Journal Reference:
- Yanhan Wang, Tissa R. Hata, Yun Larry Tong, Ming-Shan Kao, Christos C. Zouboulis, Richard L. Gallo, Chun-Ming Huang. The Anti-Inflammatory Activities of Propionibacterium acnes CAMP Factor-Targeted Acne Vaccines. Journal of Investigative Dermatology, 2018; DOI: 10.1016/j.jid.2018.05.032
New potential biotherapy for Alzheimer’s disease
Researchers at the University of Florida have discovered that a modified version of an important immune cell protein could be used to treat Alzheimer’s disease. The study, which will be published August 29 in the Journal of Experimental Medicine, reveals that soluble versions of a protein called TLR5 can reduce the buildup of amyloid plaques in the brains of Alzheimer’s disease model mice and prevent the toxic peptide that forms these plaques from killing neurons.
Alzheimer’s disease is characterized by the formation of amyloid plaques containing aggregates of a toxic protein fragment called β-amyloid that causes nerve cells in the brain to degenerate and die. The body’s immune system can influence the progression of Alzheimer’s disease by, on the one hand, reducing the buildup of β-amyloid or, on the other, responding to neuronal damage by inducing inflammation that can lead to further neurodegeneration.
Toll-like receptors (TLRs) are a family of proteins on the surface of immune cells that recognize molecules released by pathogens or damaged cells and then initiate an appropriate immune response. A team of researchers at the University of Florida led by Paramita Chakrabarty and Todd E. Golde found that the brains of Alzheimer’s disease patients had more TLRs, partly due to an increase in the number of specialized brain immune cells known as microglia.
The researchers hypothesized that untethering some of these TLRs from the surface of microglia could reduce the formation of amyloid plaques. These soluble TLRs might act as “decoy receptors” that bind to β-amyloid and limit its aggregation without initiating cellular signaling pathways that could lead to inflammation.
Chakrabarty and colleagues found that soluble versions of one TLR in particular — TLR5 — could prevent or even reverse the formation of amyloid plaques in mice that produce large amounts of human β-amyloid.
“This mouse model is well recognized as a primary model for Alzheimer-type amyloid plaque deposition, but it does not recapitulate the entire Alzheimer’s neurodegenerative cascade,” says Chakrabarty. “Therefore, the potential of soluble TLR5 in dampening immune activation and related neurotoxic pathways needs to be further explored in multiple models of Alzheimer’s disease.”
The researchers determined that soluble TLR5 could bind to β-amyloid aggregates and enhance their uptake into microglia. It also reduced the ability of β-amyloid to kill neurons cultured in the laboratory.
“By directly interacting with β-amyloid and attenuating β-amyloid levels in mice, the soluble TLR5 decoy receptor represents a novel and potentially safe class of immunomodulatory agents for Alzheimer’s disease,” says Golde.
Story Source:
Materials provided by Rockefeller University Press. Note: Content may be edited for style and length.
Journal Reference:
- Paramita Chakrabarty, Andrew Li, Thomas B. Ladd, Michael R. Strickland, Emily J. Koller, Jeremy D. Burgess, Cory C. Funk, Pedro E. Cruz, Mariet Allen, Mariya Yaroshenko, Xue Wang, Curtis Younkin, Joseph Reddy, Benjamin Lohrer, Leonie Mehrke, Brenda D. Moore, Xuefei Liu, Carolina Ceballos-Diaz, Awilda M. Rosario, Christopher Medway, Christopher Janus, Hong-Dong Li, Dennis W. Dickson, Benoit I. Giasson, Nathan D. Price, Steven G. Younkin, Nilüfer Ertekin-Taner, Todd E. Golde. TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease. The Journal of Experimental Medicine, 2018; jem.20180484 DOI: 10.1084/jem.20180484
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